The enormous diversity of neural cell types is a defining characteristic of the brain. Different neural circuits consist of a myriad of distinct cell types, each with specific intrinsic properties and patterns of synaptic connectivity, which transform neural input and convey this information to downstream targets. However, despite their fundamental importance in neural processing, our understanding of how individual cell types differentially contribute to neural circuit function and computation remains poor. Here, the investigators leverage a highly tractable neural circuit, the mouse olfactory (piriform, PCx) cortex, to determine how information about odor stimuli is encoded, transformed, and conveyed to its different downstream target areas. The objective of this proposal is to register diverse odor responses observed in PCx neurons onto identified neural cell types, defined by their morphology, intrinsic properties, and connectivity. This will be achieved via a collaborative, multidisciplinary, iterative computational-experimental approach, involving computational modeling, in vivo two photon imaging, in vitro electrophysiology, behavior, chemogenetics and decoding analyses. The investigators' working hypothesis is that different features of an odor - its identity, intensity, and valence - are selectively extracted and encoded by distinct subsets of PCx neurons by virtue of their different intrinsic and local circuit properties, and then selectively transmitted to different target areas. In the two aims proposed, the investigators will image activity evoked by different odorants at multiple concentrations in subpopulations of PCx neurons in awake, behaving mice. They will compare their imaging data with simulated odor-evoked activity in a computational model in which they incorporate the specific intrinsic properties and patterns of local synaptic connectivity of these subpopulations of PCx neurons.
In Aim1, the investigators will image and model odor responses in two morphologically distinct subtypes of principal neurons, semilunar cells and superficial pyramidal cells.
In Aim 2 they use a similar approach, but with subpopulations of PCx neurons defined by their specific projection targets. Mice will be performing a go/no go odor discrimination task during imaging, allowing characterization of responses to odors with different identities, concentrations or valence. This experimental-computational approach will determine the extent to which the distinct intrinsic properties and specific connectivity patterns of different cell-types accounts for differences in their odor responses. Crucially, mismatches between modeling and experimental results will reveal additional properties of these cells and circuitry that may determine their odor responses, which can and will be tested experimentally. Achieving the goals of this proposal will therefore provide a coherent framework for understanding how different features of an odor stimulus can be selectively extracted, encoded and conveyed to appropriate downstream targets.
The piriform cortex is implicated in a large variety of diseases. These include epilepsy, Parkinson's Disorder, schizophrenia, various dementias including Alzheimer's disease, and depression and anhedonia. It's role in all of these disorders is poorly understood. It is unlikely that piriform cortex is proximally 'responsible' for many/any of these disorders. Rather, it is likely that the function/dysfunction of distinct areas downstream of pirifrom cortex are critically affected by olfactory input. A lack of understanding of how piriform cortex is implicated in these disorders likely results, at least in part, from having considered this structure as a singular, homogenous population of neurons. This projects aims to selectively identify, characterize, and measure and manipulate the activity of different classes piriform cortex neurons defined either by their morphology or specific projection targets. This dissection of populations of piriform cortex neurons, especially by their projection targets, will likely clarify the contribution of piriform cortex inputs to multiple different disorders that grossly affect human morbidity and mortality.
